The orphan nuclear receptor TR3/Nur77 regulates ER stress and induces apoptosis via interaction with TRAPγ.

The orphan nuclear receptor TR3 (also known as Nur77) belongs to the steroid/thyroid/retinoid nuclear receptor superfamily and plays important roles in regulating cell proliferation, differentiation and apoptosis. No physiological ligand for TR3 has been found thus far; the determination of its binding partners is therefore important to clarify the biological functions of TR3. Here, we identified translocon-associated protein subunit γ (TRAPγ) as a novel TR3 binding partner using a tandem affinity purification method. This interaction between TR3 and TRAPγ was further confirmed, and the interacting regions were mapped. The ligand-binding domain of TR3 was required for TRAPγ binding, and the C terminus of TRAPγ was responsible for its interaction with TR3. When stimulated with 12-O-tetradecanoylphorbol 13-acetate (TPA) or CD437, this TR3-TRAPγ interaction not only induced Ca(2+) depletion in the endoplasmic reticulum (ER) but also promoted the expression of the proapoptotic transcriptional regulator CHOP. Notably, both TR3 and TRAPγ were required for ER stress-induced apoptosis in HepG2 cells. Overall, this study demonstrated a novel, TR3-initiated signaling pathway in which TR3 regulates ER stress and induces apoptosis of hepatoma cells through its interaction with TRAPγ.